US9763919B2 - Detecting and treating growth hormone deficiency - Google Patents

Detecting and treating growth hormone deficiency Download PDF

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US9763919B2
US9763919B2 US15/271,542 US201615271542A US9763919B2 US 9763919 B2 US9763919 B2 US 9763919B2 US 201615271542 A US201615271542 A US 201615271542A US 9763919 B2 US9763919 B2 US 9763919B2
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test
child
ghd
children
growth
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US20170079961A1 (en
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Michael Oliver Thorner
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Lumos Pharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/61—Growth hormones [GH] (Somatotropin)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/65—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2

Definitions

  • the present invention relates a new oral method for using MK-0677 for detecting growth hormone (GH) deficiency (GHD) in patients.
  • the present invention also relates to a method of treating growth hormone (GH) deficiency (GHD) in children with a functional hypothalamic-pituitary GH axis.
  • Growth hormone is an anabolic anterior pituitary hormone that stimulates cellular proliferation and differentiation through the synergistic action of GH and insulin-like growth factor-1 (IGF-1).
  • IGF-1 insulin-like growth factor-1
  • GHRH growth hormone releasing hormone
  • SST somatostatin
  • Secretion of GH is critical to normal skeletal growth during childhood, with maximum secretion occurring during puberty. Deficient secretion of GH in children results in short stature, retarded height velocity, and delayed bone maturation.
  • GFD growth hormone deficient
  • insulin induced hypoglycemia is considered the most reliable it requires that the child is supervised by a physician for the two hours that the test takes; in addition adverse effects that include two reported deaths have occurred during insulin induced hypoglycemia (REFS). For these reasons insulin induced hypoglycemia is not used by pediatric endocrinologists and the other tests are used.
  • the glucagon test is probably the most reliable but, to further enhance reliability, two tests are usually performed.
  • Recently growth hormone secretagogue receptor (GHS-R) agonists have been used and they have the advantage of being reliable but the peak GH response defining GH deficiency is poorly characterized. It would be beneficial to develop a GHD test that is easier to use, safer, and/or more reliable than the current tests.
  • MK-0677 Ibutamoren mesylate was developed at Merck Research Laboratories (Merck) as a specific orally active growth hormone secretagogue.
  • Merck conducted a phase IIb study of children with variable degrees of short stature and growth hormone deficiency (GHD) in 1996-98. They treated the children with either placebo or the growth hormone secretagogue receptor agonist MK-0677 or with rhGH (recombinant hormone growth hormone).
  • MK-0677 mimics the effect of the now recognized natural ligand for the growth hormone secretagogue receptor, which is the hormone ghrelin. The rationale was to determine whether oral therapy with MK0677 would accelerate growth effectively in children with short stature.
  • GHD leading to short stature ( ⁇ 2 SD height for chronological age) in children is a disorder found worldwide.
  • Treatment of growth hormone deficient children having short stature lasts typically for many years from diagnosis in childhood to reaching final height. Results obtained from 6 months assessment of treatment in newly-diagnosed children can be widely variable due to the differences in underlying etilology of the GH deficiency, and patterns and rates of catch-up growth on start of treatment.
  • treatment for 1 year or longer is necessary to establish a new growth trajectory on treatment. Thereafter, treatment is often required for 10 years or more, to reach an optimal adult height in these children.
  • Children with GHD are usually treated by daily subcutaneous injections of GH, which can be painful, inconvenient, and cause distress in some, especially younger, children.
  • the present invention provides a novel method of testing for GHD.
  • the present invention provides a novel method of treating GHD in children with adequate GH secretion potential.
  • the present invention provides a novel method of treating GHD in children with equivalent growth potential compared to treatment with rhGH.
  • the present invention provides novel method of testing and identifying patients for adequate GH secretion potential.
  • the present invention provides novel method of testing and identifying patients with equivalent growth potential compared to treatment with rhGH.
  • MK-0677 can be used to test for GHD as well as treat certain subpopulations of children with GHD.
  • the response to rhGH in the overall patient group is superior to MK-0677.
  • FIG. 2 compares the baseline IGF-I to acute GH response to MK-0677.
  • FIGS. 3A and 3B show the height velocity obtained for patients with low growth potential (LOW)(defined below) and equivalent growth potential in response to MK-0677 0.8 mg/k/day compared to rhGH patients (EQUAL) given GH or MK-0677, respectively.
  • FIG. 3A and FIG. 3B show that the height velocity after MK-0677 treatment for 6 months is equal to GH treatment in the EQUAL patient group.
  • FIGS. 4A and 4B compare the response to GH and MK-0677 in all patients ( FIG. 4A ) and in EQUAL patients ( FIG. 4B ).
  • the response to GH in the overall patient group is superior to MK-0677.
  • the response to MK-0677 in the EQUAL patient group is equal to GH.
  • FIGS. 5A and 5B compare the response to GH and MK-0677 in LOW and EQUAL patients.
  • LOW patients are extremely sensitive to GH.
  • EQUAL patients have a smaller response to GH.
  • LOW growth potential patients show an inadequate growth response to MK-0677.
  • the children in the equivalent growth potential group compared to rhGH (acute peak GH response of ⁇ 5 ⁇ g/L to a single dose of MK-0677 and a baseline serum IGF-I of >30 ⁇ g/L)(EQUAL patient group) responded with equivalent growth response to both exogenous GH injections and a daily oral dose of MK-0677.
  • MK-0677 By avoiding injections, once daily oral administration of MK-0677 would have many advantages as a method of treatment compared to GH injections and would allow for much easier and greater patient adherence. Since adherence is a critical component of any treatment, the ease of treatment with MK-0677 versus GH (oral versus injection) would allow a physician to choose long-term treatment with oral MK-0677 in preference to GH injections given a similar efficacy in terms of height velocity.
  • Serum IGF-1 is a biomarker of growth hormone action, and 80% of the circulating serum IGF-1 is produced in the liver.
  • baseline serum IGF-1 and peak response to standard stimulation tests clonidine, insulin, arginine, glucagon, and L-Dopa
  • r 2 0.3
  • r 2 0.7
  • the response to MK-0677 increases.
  • the peak serum GH measured during the MK-0677 challenge test (a single does of MK-0677) is robust.
  • the presence of a peak GH of ⁇ 5 ⁇ g/L indicates that the hypothalamic-pituitary GH axis can be stimulated by MK-0677 characterizing the patient as having GH secretion potential.
  • GH deficiency may be associated with profound deficiency, where the hypothalamic-pituitary GH axis is damaged and is unresponsive to MK-0677 administration.
  • dysfunction of the hypothalamic-pituitary GH axis may render the patient unable to secrete sufficient GH to sustain normal growth.
  • the MK-0677 test will determine whether they are fully deficient or if they have insufficient GH secretion and can mount a GH response indicating that the axis is responsive to MK-0677.
  • the present invention provides a novel method of treating growth hormone deficiency (GHD) in children, comprising: administering a therapeutically effective amount of MK-0677 to a child known to have short stature and adequate GH secretion potential.
  • the child is known to have growth retardation.
  • the present invention provides a novel method of treating GHD in children, comprising: administering a therapeutically effective amount of MK-0677 to a child known to have short stature and equivalent growth potential compared to rhGH.
  • the child is known to have growth retardation.
  • the present invention provides a novel method of treating GHD in children, comprising:
  • the present invention provides a novel method of treating GHD in children, comprising:
  • theranostic test comprises:
  • theranostic test further comprises:
  • pediatric GHD is treated.
  • mini-tablets comprising: MK-0677, are orally administered.
  • the number of mini-tablets can be adjusted to allow weight based dosing.
  • the orally administering further comprises: administering with the assistance of a device capable of dispensing at least one MK-0677 mini-tablet.
  • the device is also capable of at least one of the following:
  • the device is capable of: having the dosage remotely (e.g., via a wireless or wired connection to the Internet) set by a medical practitioner or via approval of the medical practitioner.
  • the hypothalamic-pituitary growth hormone axis is intact and further stimulation will increase growth.
  • the present invention also relates to treating indications outside of the standard GHD indications (e.g., pediatric GHD).
  • the present invention provides a novel method of of treating a pediatric indication, comprising:
  • the present invention provides a novel method of treating GHD in children, comprising:
  • the child is tested for adequate GH secretion potential by a method, comprising:
  • the present invention provides a novel method of treating GHD in children, comprising:
  • the child is tested for equivalent growth potential compared to rhGH by a method, comprising:
  • a method of the present invention further comprises: testing the child to determine if he or she is prepubertal and proceeding with administering if the child is found to be prepubertal in addition to the above-noted findings.
  • the method further comprises: testing the child to determine if he or she is peri-pubertal and proceeding with administering if the child is found to be peri-pubertal in addition to the above-noted findings.
  • the present invention provides a novel theranostic test for determining if a patient will be responsive to therapy with MK-0677, comprising:
  • the testing for peak serum comprises:
  • the present invention provides a novel theranostic test for determining if a patient will be responsive to therapy with MK-0677, comprising:
  • the present invention provides a novel theranostic test for diagnosing growth hormone deficiency, comprising:
  • the present invention provides a novel method of treating growth hormone insufficiency (GHI) in children, comprising: administering a therapeutically effective amount of MK-0677 to a child known to have short stature and adequate GH secretion potential.
  • the child is known to have growth retardation.
  • the present invention provides a novel method of treating GHI in children, comprising: administering a therapeutically effective amount of MK-0677 to a child known to have short stature and equivalent growth potential compared to rhGH.
  • the child is known to have growth retardation.
  • the present invention provides a novel theranostic test for diagnosing GHI, comprising:
  • the present invention provides a novel theranostic test for diagnosing GHI, comprising:
  • the present invention provides a novel method of treating GHI, comprising:
  • the test for adequate and/or equivalent GH secretion potential is an outpatient test that identifies a population of children who respond to oral MK-0677 therapy as well as to standard daily GH treatment.
  • the present invention provides MK-0677 for use in therapy.
  • the present invention provides the use of the present invention for the manufacture of a medicament for the treatment of an indication recited herein.
  • the present invention provides a novel composition comprising an active action that is MK-0677 for use in the treatment of an indication recited herein.
  • Patient refers to a human patient, either child or adult. Examples include a child, a prepubertal child, a peripubertal child, and an adult.
  • the child is known to have growth retardation.
  • the child is prepubertal.
  • the child is peripubertal.
  • Peak GH serum levels of a subject can be measured by using a well known provocative test.
  • Provocative tests are well known and include the clonidine test, insulin test, arginine test, glucagon test, and levodopa (L-dopa) test (see Example 4 below).
  • IRMA GH immunoradiometric
  • An example of the amount of MK-0677 administered is 0.8 mg/kg.
  • the patient being tested will have fasted overnight (abstinence from all food and drink but water).
  • the level of pretreatment serum IGF-I is the IGF-I level of a patient determined prior to treatment with either exogenous GH or MK-0677.
  • Child or children a male or female greater than 4 years of age.
  • Prepubertal a child having a bone age of ⁇ 8 years for female children and ⁇ 9 years for male children.
  • Bone age can be determined using a well known method such as the atlas matching method of Greulich and Pyle or the point scoring system of Tanner and Whitehouse. Other examples of bone age include ⁇ 7 for females and ⁇ 8 for males.
  • Tanner stage 1 is prepubertal and anything past that until puberty is complete (Tanner stage 4) is considered peripubertal.
  • Short Stature where a child's stature is below the 2.3 percentile ( ⁇ 2 SD height for chronological age) for his/her chronological age. Other examples include being below the 5 th , 4 th , 3 rd , 2 nd , and 1 st percentile for his/her chronological age.
  • Growth Retardation or Slow Height Velocity a height velocity less than the 25 th percentile for age and gender, as recorded over at least a 6-month period.
  • Other examples include being below the 24 rd , 23 rd , 22 nd , 21 st , 20 th , 19 th , 18 th , 17 th , 16 th , 15 th , 14 th , 13 th , 12 th , 11 th , 10 th , 9 th , 8 th , 7 th , 6 th , 5 th , 4 th , 3 rd , 2 nd , and 1 st percentile for age and gender, as recorded over at least a 6-month period.
  • Adequate GH Secretion Potential a patient is considered to have adequate GH secretion potential if the patient:
  • Equivalent growth potential compared to rhGH a patient is considered to have equivalent growth potential compared to chronic subcutaneous injections of rhGH (equivalent growth potential compared to rhGH) if the patient:
  • peak serum GH in response to a single dose of MK-0677 include ⁇ 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 and 125 ⁇ g/L.
  • Low GH secretion potential a patient is classified as having low GH secretion potential (or severely GH deficient)(LOW) if they show a peak serum GH ⁇ 5 ⁇ g/L in response to a single oral dose of MK-0677 (0.8 mg/kg).
  • 0.8 mg/kg/d of MK-0677 is administered.
  • Other examples of the amount of MK-0677 administered include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 mg/kg/d and divided doses within this range.
  • Further examples of the amount of MK-0677 administered include at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 mg/kg/d and any divided dose within this range.
  • the single, oral dose of MK-0677 is a single 0.8 mg/kg oral dose.
  • Other examples of the amount of MK-0677 administered for a test include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 mg/kg/d and divided doses within this range.
  • Further examples of the amount of MK-0677 administered for a test include at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 mg/kg/d and any divided dose within this range.
  • MK-0677 is given orally in the form of a mini tablet.
  • the mini-tablet comprises: 2 mg of MK-0677.
  • the mini-tablet comprises: from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, to 20 mg of MK-0677.
  • the mini-tablet consists essentially of: 2 mg of MK-0677.
  • the mini-tablet consists essentially of: from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, to 20 mg of MK-0677.
  • the MK-0677 mini-tablet is a small tablet that is capable of being mechanically dispensed (e.g., from a cartridge containing a plurality of tablets).
  • the largest dimension (e.g., height, width, or depth) of the mini-tablet is about 1, 2, 3, 4, to 5 mm.
  • Other examples include a largest dimension of about 2, 3, to 4 mm.
  • the largest dimension of the mini-tablet is about 3 mm.
  • the treatment is maintained for more than 6 months.
  • Other examples include treatment for at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months.
  • Further examples include treatment for at least 2.5, 3, 3.5, 4, 4.5, 5 years or until growth potential is exhausted.
  • the child to be treated has never been treated with growth hormone (na ⁇ ve).
  • the child to be treated may have received prior GH treatment that is discontinued provided that the child meets the criteria of adequate GH secretion potential as ascertained above.
  • treatment with MK-0677 may be continued to maintain normal GH secretion through adulthood.
  • the level of GH after an acute oral dose of 0.8 mg/kg of MK-0677 is ⁇ 5 ⁇ g/mL in radioimmunoassay performed by Endocrine Sciences.
  • MK-0677 was compared against placebo and rhGH injections according to the following protocol. Bone age was determined using the atlas matching method of Greulich and Pyle.
  • Protocol 6 months of once-daily oral sucrose formulation solution.
  • Peak GH to MK-0677 peak growth hormone to MK-0677 is determined by administering a single dosage of MK-0677 (0.8 mg/kg) and then measuring the peak GH resulting from the MK-0677 dosage.
  • Low Potential low GH secretion potential (excluded from present invention).
  • High Potential adequate GH secretion potential (included in present invention).
  • Prov. Test provocative test.
  • Baseline IGF-I Insulin-like Growth Factor: Can be determined by serum measurement e.g by immunoassay or liquid chromatography mass spectroscopy.
  • Table 3A shows the baseline characteristics of patients with low GH secretion potential (Peak GH to MK-0677 ⁇ 5 ⁇ g/L) who were treated with either MK-0677 (0.8 mg/kg/d) or placebo/rhGH 0.3 mg/kg/week (5 of the 24 children who received placebo for 6 months and then switched to rhGH had low GH secretion potential). Based on height velocity SD for CA, the patients treated with MK-0677 (0.8 mg/kg/day) had more growth retardation than the placebo/GH treated group. However when corrected for bone age they were similar.
  • Table 3B shows that for patients with low GH secretion potential, response to GH injections is superior than response to orally administered MK-0677.
  • Table 4A shows the baseline characteristics of patients with adequate GH secretion potential (Peak GH to MK-0677 ⁇ 5 ⁇ g/L) who were treated with either MK-0677 (0.8 mg/kg/d) or placebo/rhGH 0.3 mg/kg/week (15 of the 24 children who received placebo for 6 months and then switched to rhGH had adequate GH secretion potential.
  • Table 4B shows that for patients with adequate GH secretion potential, response to MK-0677, while being lower versus GH injections is comparable with GH and was not statistically different. This demonstrates that MK-0677 is an effective growth-promoting therapy in those GHD patients with adequate GH secretion potential
  • Table 5A shows the baseline characteristics of patients with low growth potential (Peak GH to MK-0677 ⁇ 5 ⁇ g/L) who were treated with either MK-0677 (0.8 mg/kg/d) or placebo/rhGH 0.3 mg/kg/week (9 of the 24 children who received placebo for 6 months and then switched to rhGH had low growth potential).
  • Table 5B shows the baseline characteristics of patients with high growth potential (Peak GH to MK-0677 ⁇ 5 ⁇ g/L) who were treated with either MK-0677 (0.8 mg/kg/d) or placebo/rhGH 0.3 mg/kg/week (11 of the 24 children who received placebo for 6 months and then switched to rhGH had high growth potential).
  • Tables 6A-6E show the height velocity for EQUAL growth potential children treated with either 0.8 mg/kg/daily po or 0.4 mg/kg/daily po MK-0677 compared with rhGH (0.3 mg/kg/week; ⁇ 42 ⁇ g/kg/daily sc injection).
  • LOW growth potential patients are those that do not satisfy the equivalent growth potential compared to rhGH (EQUAL) test described previously. Values are mean (SD).
  • Tables 7A-7C compare the height velocity for low growth potential patients (LOW) with equivalent growth potential compared to rhGH (EQUAL). Values are mean (SD).
  • the height velocity in the LOW group is lower than with the EQUAL group.
  • the height velocity with GH is greater in the LOW group than in the EQUAL group (see FIGS. 5A and 5B ). This is explained by greater sensitivity to GH replacement in severely GH deficient children in the rhGH treated children.
  • the LOW growth potential children are unable to secrete enough endogenous GH to sustain the same height velocity compared to exogenous rhGH injections while in the EQUAL growth potential patients they are able to secrete enough endogenous GH to produce the same growth response as to daily exogenous rhGH injections.
  • MK-0677 Dosages of MK-0677 for Growth Hormone Deficient Children MK-0677 Dose Number of 2-mg Subject's Weight 0.8 mg/kg/day Mini-tablets 15 kilograms to ⁇ 20 kilograms 12 mg 6 20 kilograms to ⁇ 25 kilograms 16 mg 8 25 kilograms to ⁇ 30 kilograms 20 mg 10 30 kilograms to ⁇ 35 kilograms 24 mg 12 35 kilograms to ⁇ 40 kilograms 28 mg 14 40 kilograms to ⁇ 45 kilograms 32 mg 16 >45 kilograms 36 mg 18
  • the rank ordering of the IGF1 and peak GH stimulated by MK-0677 are very similar, with a Spearman correlation of 0.82.
  • GH cutpoint of 7 or 8 ⁇ g/L use a MK-0677 cutpoint of 35 ⁇ g/L
  • Subjects will report to the clinic in the morning after an overnight fast from all food and drink except water.
  • a catheter will be inserted approximately 1 hour before the administration of MK 0677.
  • Subjects will be given a dose of 0.8 mg/kg MK-0677 as 2-mg tablets to be taken orally.
  • the catheter will be removed. All blood samples will be analyzed for GH, prolactin, and cortisol by a core clinical laboratory.
  • the patient should also be subjected to a provocative GH test.
  • provocative GH test include the known Clonidine Test, Insulin Test, Arginine Test, Glucagon Test, and Levodop (L-dopa) test. Examples of test protocols for these tests are provided below.
  • a catheter will be inserted at least 1 hour prior to the administration of clonidine.
  • the risks associated with clonidine testing include possible hypotensive side effects and somnolence.
  • a catheter should be inserted at least 1 hour prior to the administration of insulin.
  • One-tenth unit kilograms of insulin will be injected.
  • Insulin testing will only be considered successful if the blood sugar level decreases to at least half of its fasting value. Possible risks of this test include palpitations, tremors, severe hypoglycemia, seizures, and in some instances, death.
  • Glucose and glucagon should be prepared and be available for injection in the event of an emergency. An experienced physician should be at the bedside throughout the test to monitor for side effects. At the conclusion of the test, patient should be given a meal immediately.
  • a catheter and an IV should be inserted 1 hour prior to the administration of arginine.
  • Arginine should be given at a dose of 0.5 g/kg with a maximum dose not to exceed 30 g.
  • a catheter should be inserted at least 1 hour prior to the administration of glucagon.
  • Glucagon will be given as an intramuscular injection at a dose of 1 mL for patients weighing 10 to 35 kilograms.
  • a catheter will be inserted at least 1 hour prior to the administration of L-dopa.
  • Two-hundred and fifty milligrams of L-dopa will be administered in tablet form to patients weighing 15 to 30 kilograms and 500 milligrams of L-dopa will be administered orally in tablet form to patients weighing more than 30 kilograms.

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US10288629B1 (en) * 2017-12-19 2019-05-14 Aeterna Zentaris, Inc. Method of assessing growth hormone deficiency in humans by a macimorelin containing composition
US11234969B2 (en) * 2016-01-30 2022-02-01 Lumos Pharma, Inc. Detecting and treating growth hormone deficiency
US11644474B2 (en) * 2020-07-22 2023-05-09 Æterna Zentaris Gmbh Use of macimorelin in assessing growth hormone deficiency in children
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10105352B2 (en) * 2015-09-21 2018-10-23 Lumos Pharma, Inc. Detecting and treating growth hormone deficiency
US11234969B2 (en) * 2016-01-30 2022-02-01 Lumos Pharma, Inc. Detecting and treating growth hormone deficiency
US10288629B1 (en) * 2017-12-19 2019-05-14 Aeterna Zentaris, Inc. Method of assessing growth hormone deficiency in humans by a macimorelin containing composition
US11644474B2 (en) * 2020-07-22 2023-05-09 Æterna Zentaris Gmbh Use of macimorelin in assessing growth hormone deficiency in children
US11969416B1 (en) 2022-11-03 2024-04-30 Lumos Pharma, Inc. Compactable oral formulations of ibutamoren

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